PI3Kγ is a molecular switch that controls immune suppression
Megan M. Kaneda,Karen Messer,Natacha Ralainirina,Hongying Li,Christopher J. Leem,Sara Gorjestani,Gyunghwi Woo,Abraham V. Nguyen,Camila C. Figueiredo,Camila C. Figueiredo,Philippe Foubert,Michael C. Schmid,Melissa Pink,David G. Winkler,Matthew Rausch,Vito J. Palombella,Jeffery L. Kutok,Karen McGovern,Kelly A. Frazer,Xuefeng Wu,Michael Karin,Roman Sasik,Ezra E.W. Cohen,Judith A. Varner +23 more
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TLDR
This work demonstrates that therapeutic targeting of intracellular signalling pathways that regulate the switch between macrophage polarization states can control immune suppression in cancer and other disorders.Abstract:
Macrophages play critical, but opposite, roles in acute and chronic inflammation and cancer. In response to pathogens or injury, inflammatory macrophages express cytokines that stimulate cytotoxic T cells, whereas macrophages in neoplastic and parasitic diseases express anti-inflammatory cytokines that induce immune suppression and may promote resistance to T cell checkpoint inhibitors. Here we show that macrophage PI 3-kinase γ controls a critical switch between immune stimulation and suppression during inflammation and cancer. PI3Kγ signalling through Akt and mTor inhibits NFκB activation while stimulating C/EBPβ activation, thereby inducing a transcriptional program that promotes immune suppression during inflammation and tumour growth. By contrast, selective inactivation of macrophage PI3Kγ stimulates and prolongs NFκB activation and inhibits C/EBPβ activation, thus promoting an immunostimulatory transcriptional program that restores CD8+ T cell activation and cytotoxicity. PI3Kγ synergizes with checkpoint inhibitor therapy to promote tumour regression and increased survival in mouse models of cancer. In addition, PI3Kγ-directed, anti-inflammatory gene expression can predict survival probability in cancer patients. Our work thus demonstrates that therapeutic targeting of intracellular signalling pathways that regulate the switch between macrophage polarization states can control immune suppression in cancer and other disorders.read more
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References
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Journal ArticleDOI
Macrophage plasticity and polarization: in vivo veritas
Antonio Sica,Alberto Mantovani +1 more
TL;DR: The identification of mechanisms and molecules associated with macrophage plasticity and polarized activation provides a basis for Macrophage-centered diagnostic and therapeutic strategies.
Journal ArticleDOI
The future of immune checkpoint therapy
Padmanee Sharma,James P. Allison +1 more
TL;DR: The way forward for this class of novel agents lies in the ability to understand human immune responses in the tumor microenvironment, which will provide valuable information regarding the dynamic nature of the immune response and regulation of additional pathways that will need to be targeted through combination therapies to provide survival benefit for greater numbers of patients.
Journal ArticleDOI
Macrophage biology in development, homeostasis and disease
TL;DR: This Review discusses how macrophage regulate normal physiology and development, and provides several examples of their pathophysiological roles in disease, and defines the ‘hallmarks’ of macrophages according to the states that they adopt during the performance of their various roles.
Journal ArticleDOI
Immune checkpoint blockade: a common denominator approach to cancer therapy
TL;DR: The immune system recognizes and is poised to eliminate cancer but is held in check by inhibitory receptors and ligands, so drugs interrupting immune checkpoints, such as anti-CTLA-4, anti-PD-1, and others in early development, can unleash anti-tumor immunity and mediate durable cancer regressions.
Journal ArticleDOI
CSF-1R inhibition alters macrophage polarization and blocks glioma progression
Stephanie M. Pyonteck,Leila Akkari,Alberto J. Schuhmacher,Robert L. Bowman,Lisa Sevenich,Daniela F. Quail,Oakley C. Olson,Marsha L. Quick,Jason T. Huse,Virginia Teijeiro,Manu Setty,Christina S. Leslie,Yoko Oei,Alicia Pedraza,Jianan Zhang,Cameron Brennan,James Sutton,Eric C. Holland,Dylan Daniel,Johanna A. Joyce +19 more
TL;DR: The results identify TAMs as a promising therapeutic target for proneural gliomas and establish the translational potential of CSF-1R inhibition for GBM.
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